A chemist in search of efficacious pharmaceuticals benefits greatly when a reaction in introduced that results in the regio-and stereoselective formation of ubiquitous bonds (e.g., carbon-carbon bonds). To this end, the design and development of new chemical reactions-reactions that are otherwise unavailable-take on an added significance. The objective of this proposal is to develop the metal-catalyzed alkene addition of alkyl magnesium reagents into a general regio-and stereoselective method for formation of carbon-carbon bonds. Such processes constitute a new and valuable transformation: the addition of a carbon nucleophile onto an unactivated olefin. A special advantage of the transition metal-catalyzed carbomagnesation is that the reactions can be effected with high turnover numbers, in a truly catalytic and not stoichiometric fashion. The directed variant of the Zr-catalyzed carbomagnesation, as a method for the regio- and stereoselective formation of C-C bonds, will be examined. The practical utility of this class of reactions will be demonstrated by the preparation of structurally diverse and nonproteogenic alpha-amino acids. The asymmetric total synthesis of the novel and potent macrolactam antifungal agent sch 38516 (not accessible through fermentation) and a number of its derived analogs will be undertaken. (The resulting synthetic compounds will be tested at the Schering-Plough company.) The intramolecular version of the reaction as a strategy to augment selectivity and reactivity will be explored. The synthetic utility of this class of reactions will be demonstrated by a convergent and stereoselective preparation of the acyclic segment of the antitumor agent macbecin-1. Another objective of this proposal will be the development of the asymmetric version of the transition metal-catalyzed carbomagnesations. Our studies will be guided by the principle that internal Lewis base directivity is crucial for the effective transfer of chirality from the catalyst to the substrate. The experiments outlined herein will develop the metal-catalyzed carbomagnesation into a general and selective method for the formation of C-C bonds. The addition of magnesium-alkyls to unactivated olefins is an unattainable transformation without catalysis. Once accessible, this reaction will be of value in the synthesis of complex organic molecules. Most importantly, given the often largely disparate biological activities of enantiomers, the development of the enantioselective variant of this process will be of further significance to pharmacology and therapeutics.